Arthritis and rheumatism vol:62 issue:12 pages:3595-3606
OBJECTIVE.: CD248 is a transmembrane glycoprotein expressed on the surface of activated perivascular and fibroblast-like cells. We explored the function of CD248 and its cytoplasmic domain in arthritis. METHODS.: Synovial tissue biopsies from healthy controls and patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) were stained for CD248. Transgenic mice that are CD248-deficient (CD248(KO/KO)) or lack the cytoplasmic domain of CD248 (CD248(CyD/CyD)) were generated. Collagen antibody-induced arthritis (CAIA) was induced in these mice and corresponding wild type mice. Clinical signs and histological features of arthritis were evaluated. Cytokine levels were determined by enzyme-linked immunosorbent assay and the number of infiltrating inflammatory cells was quantified by immunohistochemistry. In vitro studies were performed with fibroblasts from CD248 transgenic embryos to explain the observed effects on inflammation. RESULTS.: Immunostaining of synovium from patients with PsA and RA and from mice after CAIA revealed strong CD248 expression in perivascular and fibroblast-like stromal cells. CD248(KO/KO) and CD248(CyD/CyD) mice had less severe arthritis, with lower plasma levels of proinflammatory cytokines. Their joints had less synovial hyperplasia, reduced accumulation of inflammatory cells, and less articular cartilage and bone damage. Tumor necrosis factor (TNF)-alpha-induced monocyte adhesion to CD248(CyD/CyD) fibroblasts was impaired. CD248(CyD/CyD) fibroblasts exhibited reduced expression of hypoxia inducible factor (HIF) 1-alpha, placental growth factor (PlGF), vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 activity in response to transforming growth factor (TGF)-beta. CONCLUSION.: CD248 contributes to synovial hyperplasia and leukocyte accumulation in inflammatory arthritis, effects that are mediated partly via its cytoplasmic domain. CD248 is therefore a potential new target to treat arthritis.